Non-immunogenicity of overlapping Gag peptides pulsed on autologous cells after vaccination of HIV infected individuals
Open accessAbstract
BACKGROUND: HIV Gag-specific CD4+ and CD8+ T-cell responses are important for HIV immune control. Pulsing overlapping Gag peptides on autologous lymphocytes (OPAL) has proven immunogenic and effective in reducing viral loads in multiple pigtail macaque studies, warranting clinical evaluation. METHODOLOGY: We performed a phase I, single centre, placebo-controlled, double-blinded and dose-escalating study to evaluate the safety and preliminary immunogenicity of a novel therapeutic vaccine approach 'OPAL-HIV-Gag(c)'. This vaccine is comprised of 120 15mer peptides, overlapping by 11 amino acids, spanning the HIV Gag C clade sequence proteome, pulsed on white blood cells enriched from whole blood using a closed system, followed by intravenous reinfusion. Patients with undetectable HIV viral loads (<50 copies/ml plasma) on HAART received four administrations at week 0, 4, 8 and 12, and were followed up for 12 weeks post-treatment. Twenty-three people were enrolled in four groups: 12 mg (n = 6), 24 mg (n = 7), 48 mg (n = 2) or matching placebo (n = 8) with 18 immunologically evaluable. T-cell immunogenicity was assessed by IFNγ ELIspot and intracellular cytokine staining (ICS). RESULTS: The OPAL-HIV-Gag(c) peptides were antigenic in vitro in 17/17 subjects. After vaccination with OPAL-HIV-Gag(c), 1/6 subjects at 12 mg and 1/6 subjects at 24 mg dose groups had a 2- and 3-fold increase in ELIspot magnitudes from baseline, respectively, of Gag-specific CD8+ T-cells at week 14, compared to 0/6 subjects in the placebo group. No Gag-specific CD4+ T-cell responses or overall change in Rev, Nef, Tat and CMV specific responses were detected. Marked, transient and self-limiting lymphopenia was observed immediately post-vaccination (4 hours) in OPAL-HIV-Gag(c) but not in placebo recipients, with median fall from 1.72 to 0.67 million lymphocytes/mL for active groups (P<0.001), compared to post-placebo from 1.70 to 1.56 lymphocytes/ml (P = 0.16). CONCLUSION/SIGNIFICANCE: Despite strong immunogenicity observed in several Macaca nemestrina studies using this approach, OPAL-HIV-Gag(c) was not significantly immunogenic in humans and improved methods of generating high-frequency Gag-specific T-cell responses are required. NAME OF REGISTRY: ClinicalTrials.gov, Registry number: NCT01123915, URL trial registry database: http://www.clinicaltrials.gov/ct2/results?term=OPAL-HIV-1001&Search=Search.
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The transient lymphopenia changes were not considered to represent toxicity but rather redistribution of lymphocytes due to the vaccine's mode of action, as has been observed for other vaccines.
“These transient changes were not considered to represent toxicity but rather redistribution of lymphocytes due to the vaccine’s mode of action as has been observed for other vaccines [12], [13].”
From Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial (2021) · cites this paper as [13]
The Results section reports transient lymphopenia after OPAL-HIV-Gag(c) vaccination, and the Discussion says the rapid recovery suggests redistribution of lymphocytes. The paper presents redistribution as an inference, not an established mechanism; the passages do not explicitly classify the changes as non-toxic or say they were observed with other vaccines. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRabies virus-specific serum neutralizing titers were measured using the WHO-recommended rapid fluorescent focus inhibition test (RFFIT) at the accredited Kansas State University Rabies Laboratory.
“Rabies virus-specific serum neutralizing titers (VNT) were measured using the WHO-recommended rapid fluorescent focus inhibition test (RFFIT) [13] at the accredited Kansas State University Rabies Laboratory.”
From Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial (2021) · cites this paper as [13]
The Methods sections describe HIV Gag-specific IFNγ ELIspot and intracellular cytokine staining assays, not rabies-virus neutralization testing. Searches for RFFIT, rabies neutralizing titers, WHO guidance, and the Kansas State University Rabies Laboratory found no passage addressing the cited method. (LLM, conf=0.76)
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Aldrich, C., Leroux–Roels, I., Huang, K. B., Bica, M. A., Loeliger, E., Schoenborn-Kellenberger, O., Walz, L., Leroux-Roels, G., von Sonnenburg, F., & Oostvogels, L. (2021) · Vaccine · doi:10.1016/j.vaccine.2020.12.070 · Cited by 204 · see citing works
“Safety and reactogenicity were assessed up to 28 days post-vaccination using diary cards; immunogenicity was measured as RABV-G-specific neutralizing titers (VNT) by RFFIT and IgG by ELISA.”
MethodResultMohamed, H., Berman, R. E., Connors, J. R., Haddad, E. K., Miller, V., Nonnemacher, M. R., Dampier, W., Wigdahl, B. L., & Krebs, F. C. (2023) · Biomedicines · doi:10.3390/biomedicines11010122 · Cited by 8 · see citing works
- Authors
- Kløverpris, H. N., Jackson, A., Handley, A., Hayes, P., Gilmour, J., Riddell, L., Chen, F., Atkins, M., Boffito, M., Walker, B. D., Ackland, J., Sullivan, M., & Goulder, P.
- Affiliations
- University of Copenhagen (DK)
- Chelsea and Westminster Hospital (GB)
- Imperial College London (GB)
- National Health Service (GB)
- Royal Berkshire Hospital (GB)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Corresponding author
- Kløverpris, Henrik N.
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-10-04
- Volume
- 8
- Issue
- 10
- Pages
- e74389
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3790804
- OpenAlex
- W2171833910
- Cited by
- 2
- References
- 44
- Citations by year
- 2023: 1 · 2021: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- International AIDS Vaccine Initiative
- Massachusetts General Hospital
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- HIV infection, CD8+ T cell responses, CD4+ T cell responses, vaccine immunogenicity, vaccine safety, lymphopenia, viral load, highly active antiretroviral therapy, dose escalation, interferon-gamma
- MeSH terms
- Adolescent, Adult, Female, Humans, Interferon-gamma, Male, Middle Aged, CD4-Positive T-Lymphocytes, HIV Infections, AIDS Vaccines, CD8-Positive T-Lymphocytes, Young Adult
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